Benzodiazepine Discontinuation and Mortality Among Patients Receiving Long-Term Benzodiazepine Therapy

Key Points Question Given the association of benzodiazepine receipt with patient harms, does prescription discontinuation reduce risk of death and other harms in patients receiving stable long-term benzodiazepine treatment? Findings In this comparative effectiveness study among 353 576 patients receiving stable long-term treatment with benzodiazepines, discontinuation was associated with small absolute increases in mortality and other potential harms, including nonfatal overdose, suicide attempt, suicidal ideation, and emergency department visits. Meaning These results suggest benzodiazepine discontinuation among patients prescribed for stable long-term treatment may be associated with unanticipated harms, and that efforts to promote discontinuation should carefully consider the potential risks of discontinuation relative to continuation.


Introduction
Over 10% of US adults reported past-year prescription benzodiazepine use from 2015-2016, 1 with the prevalence and total volume of prescribing having grown over the prior 2 decades. 2 After opioids, benzodiazepine are the medication most involved in prescription overdose (OD) deaths 3 ; by 2020, the US had the highest ever number of benzodiazepine-involved OD deaths. 4The growth in use and associated harms may account for increased attention from the US Food and Drug Administration (FDA), with a 2016 warning related to coprescribing with opioids 5 ; a 2020 class-wide boxed warning regarding "the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions" 6 ; and an Evidence-Based Clinical Practice Guideline for the Safe Tapering of Benzodiazepines in progress. 7][10] While extensive evidence characterizes the risks associated with benzodiazepine use, 3,[11][12][13][14] no studies have focused explicitly on discontinuation risks.6][17][18][19] In fact, cessation of treatment may be particularly fraught for benzodiazepine: psychologically, because many patients find the prospect of discontinuation distressing, 20,21 and physiologically, because of physical dependence and the potential for withdrawal, including seizures. 8,22,23 inform benzodiazepine policy and guidelines, we sought to determine the cumulative risks or benefits associated with benzodiazepine discontinuation.We did so using an emulated target trial approach in national claims data 24 by identifying a population of patients receiving stable long-term benzodiazepine treatment and estimating the association of discontinuation with all-cause mortality and other potential associated harms.Given the increased mortality associated with coprescribed opioids and benzodiazepine, we stratified analysis by opioid use to inform decision-making for patients coprescribed opioids.We hypothesized that prescription benzodiazepine discontinuation would be associated with reduced risk of mortality and other adverse events.

Study Design and Data Source
We used a commercial US health claims database (Optum) for 2013 through 2019 to conduct an analysis examining the association between benzodiazepine discontinuation and mortality, nonfatal overdose, suicide attempt or self-inflicted injury, suicidal ideation, and emergency department use among long-term benzodiazepine users.The deidentified health claims data represent a large sample from across the US, including commercially insured (ie, working age) and Medicare Advantage (ie, older adult) beneficiaries.The study was approved by the Michigan Medicine institutional review board for retrospective analysis of deidentified secondary data with a waiver of informed consent and followed the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) reporting guidelines.

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Discontinuation and Mortality Among Patients With Long-Term Benzodiazepine Therapy

Eligibility Criteria
We established a cohort of adults with stable long-term benzodiazepine consumption by identifying all benzodiazepine prescriptions filled between January 1, 2013, and December 31, 2019, using pharmacy claims (hereafter, index fills) (eFigure in Supplement 1).We restricted to index fills where the patient was alive and had continuous insurance coverage for the next 365 days, which was the baseline period.We excluded patients with fills for liquid benzodiazepine given difficulties computing average daily dose in lorazepam-equivalent doses for liquid benzodiazepine prescriptions. 25 limit the cohort to long-term benzodiazepine use, we used prescription fill dates and days dispensed to restrict index fills to those with benzodiazepine coverage for 90% of days or more during the baseline year and no gaps in benzodiazepine coverage greater than 30 consecutive days.
We required long-term use to reflect a relatively consistent, continuous level of benzodiazepine exposure so that discontinuation (described in "Treatment Strategies and Assignment") represented a marked change in treatment.Finally, to limit the cohort to stable long-term therapy, we further limited to those with index fills followed by a year-long baseline with monthly average daily doses within 30% of the baseline grand mean using lorazepam-equivalent doses. 25We removed index fills where the patient was younger than 18 years, received hospice care during baseline, or had cancer (except nonmelanoma skin cancer), a seizure disorder, or a nonfatal overdose during baseline (eTable 1 in Supplement 1).
We removed patients missing key variables or a baseline average daily benzodiazepine dose greater than the 99th percentile (15.8 lorazepam-equivalent mg/d).These doses may have resulted from data error, but if accurate, patients receiving such high-dose therapy would require an alternative discontinuation approach.We emulated the trial separately for those recently exposed to opioids (ie, received 1 or more opioid fill during the last 30 days of baseline) to examine the effect size associated with discontinuation by baseline opioid use status.Finally, within each potentially eligible target population receiving stable long-term benzodiazepine therapy, a given patient could have multiple index fills; we randomly selected 1 index fill per patient. 24

Outcome and Follow-Up
The primary outcome was all-cause mortality.Follow-up started immediately after the end of baseline year, was 360 days long (allowing twelve 30-day months), and ended the month during which the outcome was observed or insurance disenrollment occurred, whichever came first (Figure 1).Because only month and year of death are available in the data (for deidentification purposes), we randomly assigned day of death within the month of death, assuming a uniform distribution across days. 26Although we used discrete time survival methods (discretized to month), we assigned a date of death to ascertain if death occurred before or after benzodiazepine discontinuation.

Treatment Strategies and Assignment
An outlined protocol of the target trial we sought to emulate is presented in Table 1.We compared 2 treatment strategies: (1) discontinuation from stable long-term benzodiazepine therapy or (2)   continued benzodiazepine prescribing.8][29][30][31] Patients were considered discontinued beginning on the 31st consecutive day with no benzodiazepine coverage.We used the clone-censor-weight approach to overcome immortal time and other biases potentially present when time anchors overlap, such as during the treatment assignment period and follow-up here. 24,32We created 2 clones for each patient, where 1 was assigned to the discontinued benzodiazepine group and the other to the continued benzodiazepine group.We censored clones when their observed benzodiazepine fills were no longer consistent with the assigned treatment strategy.For patients who did not discontinue benzodiazepine during the grace period, their discontinued benzodiazepine clone was censored at the end of the grace period, and 1 clone per

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Discontinuation and Mortality Among Patients With Long-Term Benzodiazepine Therapy patient remained at the end of the grace period.Under the clone-censor-weight approach, events that occur during the grace period but prior to either clone being censored are attributed to both groups.

Estimates of Effect Sizes
We estimated both intention-to-treat and per-protocol effect sizes of discontinuation from stable long-term benzodiazepine prescribing on our outcomes of interest.When estimating the intent-totreat effect sizes, once a patient was assigned to a single treatment group, they were assigned to the group for the entirety of follow-up regardless of treatment adherence status.In contrast, when estimating the per-protocol effect sizes, after each patient was assigned to a single treatment group, we censored when they were no longer adherent to the assigned treatment.

Potential Confounders
We adjusted for the following potential confounding factors, measured during baseline: age; sex; race and ethnicity; census region; year at start of follow-up; average daily lorazepam-equivalent benzodiazepine dose; anxiety; depression; long-term noncancer pain; insomnia; bipolar disorder; other psychotic disorders; substance use disorders (alcohol, opioid, cocaine and stimulants, sedatives, cannabis, and other substances); a modified Elixhauser comorbidity score (excluding mental health conditions captured separately); and 30-day supplies of antidepressants, antipsychotics, antiepileptics, and nonbenzodiazepine benzodiazepine receptor agonists (eTables 2 and 3 in Supplement 1).Race and ethnicity is provided within the claims database (Asian, Black, Hispanic, White, unknown, or missing) and was included to capture unmeasured social factors, including the experience of racism.

Statistical Analysis
To allow for potential differences in the association between discontinuation from stable long-term benzodiazepine use and mortality by opioid use, all analyses were stratified by opioid use.We examined the association between discontinuation from stable long-term benzodiazepine prescriptions and mortality using discrete time survival analysis and fitting a weighted pooled logistic regression model with treatment group, month (included as linear, quadratic, and cubic terms), and

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Discontinuation and Mortality Among Patients With Long-Term Benzodiazepine Therapy interaction terms between treatment group and month.We estimated 3 sets of time-varying weights: (1) a treatment assignment weight to adjust for informative censoring of clones during the grace period, (2) a loss-to-follow-up weight to adjust for possible selection bias due to insurance disenrollment, and (3) a treatment adherence weight (only for per-protocol analysis) to adjust for confounding related to nonadherence.Each weight was estimated separately as the inverse probability of remaining uncensored at each month for each patient given potential confounders, and the probability of remaining uncensored up to the month was calculated as the cumulative product of the monthly weights (eMethods in Supplement 1).We truncated the final weight at the 99th percentile.
After fitting the weighted logistic regression model, we computed and plotted the standardized cumulative incidence by treatment group.Additionally, we calculated the risk difference and risk ratio to compare benzodiazepine discontinuation with continuation 12 months after baseline.We estimated percentile-based 95% CIs using bootstrapping with 100 samples.Significance was set at α = .05;tests were 2-sided.Analysis was conducted using SAS Enterprise Guide version 8.1 (SAS Institute).
We repeated the analysis for the following secondary outcomes: nonfatal overdose; suicide attempt or self-inflicted injury; suicidal ideation; and any emergency department use (eTable 4 in Supplement 1).For secondary outcomes, the loss-to-follow-up weight to account for disenrollment also accounted for death.Given potential age differences in risk, we conducted a secondary analysis of the primary outcome in age subgroups.Lastly, we performed a sensitivity analysis of the primary outcome by defining benzodiazepine discontinuation as 61 consecutive days without benzodiazepine coverage.

Results
There

Intention-to-Treat Results
Characteristics of stable long-term benzodiazepine users in the intention-to-treat analysis are presented in ).After applying the clone-censor-weight approach, these imbalances were largely mitigated (eTables 5 and 6 in Supplement 1).

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Discontinuation and Mortality Among Patients With Long-Term Benzodiazepine Therapy a Discontinuation is defined as 31 consecutive days without prescription benzodiazepine coverage.Characteristics presented here from the end of the grace period, by which time each patient has a maximum of 1 clone remaining; overall totals differ from the Abstract and flow chart, which include patients who contributed to outcomes but were censored by the end of the grace period.
b Opioid exposure is defined as the presence of at least one prescription opioid fill during the last 30 days of the baseline period.
c The Elixhauser score is modified to exclude depression, substance abuse, alcohol abuse, and psychosis as these are included as separate covariates.

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Discontinuation and Mortality Among Patients With Long-Term Benzodiazepine Therapy Among those with opioid exposure, the adjusted cumulative incidence of death 1 year after start of follow-up was higher, at 6.3% (95% CI, 6.0%-6.6%)for discontinuers and 3.9% (95% CI, 3.8%-4.1%)for nondiscontinuers.The absolute risk difference estimate was 2.4 percentage points (95% CI, 2.2-2.7 percentage points) higher among those who discontinued benzodiazepine vs not, yielding a mortality risk at 12 months for discontinuers 1.6 (95% CI, 1.5-1.7)times that of nondiscontinuers.The relative risk of mortality was similar in analyses with subgroups for both age and opioid use (eTable 7 in Supplement 1).

Per-Protocol Results
Characteristics of stable long-term benzodiazepine users at the end of the grace period for the per-protocol analysis are presented in eTable 8 in Supplement Balance across treatment groups was similar for those with opioid exposure.After applying the clone-censor-weight approach, these small imbalances were mitigated (eTables 9 and 10 in Supplement 1).
Per-protocol results are presented in eTable 11 in Supplement 1.For all outcomes, discontinuers were at higher risk than nondiscontinuers, and the risks were higher than in the intention-to-treat approach.Correspondingly, risk ratios were higher among discontinuers overall, and slightly higher than found in the intention-to-treat approach.

Sensitivity Analysis Results
Results where we defined discontinuation as 61 consecutive days of no benzodiazepine coverage were consistent with the primary analysis.A cumulative incidence of mortality after 1 year was higher among discontinuers than nondiscontinuers in both the intention-to-treat and per-protocol analyses, and higher among those with recent opioid exposure than those without (eTable 12 in Supplement 1).

Figure 1 .
Figure 1.Study Design for Target Trial Emulation of Discontinuation From Long-Term Stable Benzodiazepine Prescriptions

Figure 2 .
Figure 2. Standardized Cumulative Incidence Curves Examining the Association Between Benzodiazepine Discontinuation and Mortality, Stratified by Opioid Exposure

Table 1 .
Protocol of the Target Trial and Emulation Examining Discontinuation of Benzodiazepines Among Patients Prescribed Stable Long-term Benzodiazepine Therapy , race, census region, average benzodiazepine use in lorazepam-equivalent units, year at start of follow-up, medication use during baseline, modified Elixhauser score, mental health and clinical comorbidities Age, sex, race, census region, average benzodiazepine use in lorazepam-equivalent units, year at start of follow-up, medication use during baseline, modified Elixhauser score, mental health and clinical comorbidities Medication use by class (No. of 30-day supplies) Opioid use during last 30 days of baseline only Baseline period (365 Days beginning on the index fill date) Month (360 days) a Analyses stratified by baseline opioid use.

Table 2 .
Among patients without recent opioid exposure, treatment groups were

Table 2 .
Characteristics of Patients Prescribed Stable Long-Term Benzodiazepine Therapy Stratified by Opioid Exposure at the End of the Grace Period for the Intention-to-Treat Analysis, Overall and by Benzodiazepine Discontinuation Status a

Table 3 .
Mortality and Secondary Outcomes by Treatment Strategy Among Patients Prescribed Stable Long-Term Benzodiazepine Therapy, Stratified by Opioid Exposure in the Intention-to-Treat Approach Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy without Baseline Opioid Use at the End of the Grace Period, Overall and by Discontinuation Status: Before and After Weighting in the Intention-to-Treat Analysis eTable 6. Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy with Baseline Opioid Use at the End of the Grace Period, Overall and by Discontinuation Status: Before and After Weighting in the Intention-to-Treat Analysis eTable 7. Results of a Secondary Analysis Examining Benzodiazepine Discontinuation and Mortality Risk Among Patients Prescribed Stable Long-term Benzodiazepine Therapy, Stratified by Age, Intention-to-Treat Analysis eTable 8. Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy Stratified by Opioid Exposure at the End of the Grace Period for the Per-Protocol Analysis, Overall and by Benzodiazepine Discontinuation Status eTable 9. Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy without Opioid Exposure at the End of the Grace Period, Overall and by Discontinuation Status: Before and After Weighting in the Per-Protocol Analysis eTable 10.Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy with Opioid Exposure at the End of the Grace Period, Overall and by Discontinuation Status: Before and After Weighting in the Per-Protocol Analysis eTable 11.Adjusted Incidence, Risk Difference, and Risk Ratio of Mortality and Secondary Outcomes Among Patients Prescribed Stable Long-term Benzodiazepine Therapy, Stratified by Opioid Exposure, by Treatment Strategy eTable 12. Results of Sensitivity Analysis Examining Benzodiazepine Discontinuation and Mortality Risk Among Patients Prescribed Stable Long-term Benzodiazepine Therapy, Stratified by Opioid Use b Discontinuation is defined as 31 consecutive days without prescription benzodiazepine coverage.cOpioid exposure is defined as the presence of at least 1 prescription opioid fill during the last 30 days of the baseline period.